Satellite Symposium at the American Heart Association Meeting 2013

Sunday, Nov. 17, 2013

Robert A. Kloner, MD, PhDProfessor of Medicine

Keck School of Medicine at USCDirector of Research

Heart InstituteGood Samaritan Hospital

Los Angeles, CA Disclosure: Dr. Kloner is a consultant to IC Therapeutics, Speaker and consultant to Gilead , and

Consultant and receives grant support from Stealth Peptides, Inc. and Boehringer Iingelheim.

Introduction to the Concepts of Ischemic Conditioning

The Preconditioning Phenomenon

The heart’s own self-preserving mechanismBrief periods of ischemia (2-5 minutes) prior to a longer duration

of ischemia: Reduce infarct size in most models Reduce ventricular arrhythmiasIf we can learn the mechanism of preconditioning, it may lead to

potentially important therapies.

Effects of preconditioning on myocardial infarct size in dogs

Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay oflethal cell injury in ischemic myocardium. Circulation. 1986 Nov;74(5):1124-36

Clinical Evidence For Preconditioning

• Less chest pain, ST-segment elevation, lactate production with subsequent compared to first angioplasty balloon inflation

• Reduction in infarct size, mortality and CHF in patients with history of angina before acute MI

• Acute tolerance to angina (warm up phenomenon)• Studies performed on human cardiac tissue:

– ATP levels during CABG– In vitro studies on isolated human muscle– In vitro studies on human myocytes

History of Any Angina - TIMI 4

No Angina Angina

To

tal

CK

un

its

0

100

120

140

160

Kloner, et al.

154

119

Kloner RA, Shook T, Przyklenk K, Davis VG, Junio L, Matthews RV, Burstein S,Gibson M, Poole WK, Cannon CP, McCabe C, Braunwald E, for the TIMI 4 Investigators. Previous angina alters in-hospital outcome in TIMI 4. A clinical correlate to preconditioning? Circulation 1995; 91:37-45.

History of Any Angina - TIMI 4

(%)

0

2

4

6

8

10

12

14No AnginaAngina

8%

3%

7%

1%

12%

4%p = 0.03

p = 0.006

p = 0.004

In-Hospital Death

Severe CHF/ Shock

DeathSevere CHF Shock

Kloner RA, Shook T, Przyklenk K, Davis VG, Junio L, Matthews RV, Burstein S,Gibson M, Poole WK, Cannon CP, McCabe C, Braunwald E, for the TIMI 4 Investigators. Previous angina alters in-hospital outcome in TIMI 4. A clinical correlate to preconditioning? Circulation 1995; 91:37-45.

Postconditioning

Postconditioning is the phenomenon whereby several brief coronary artery reperfusion/reocclusion cycles at the end of a long coronary artery occlusion (stuttering reperfusion) reduces infarct size

• Zhao, Z-Q et al. Am J Physiol 2003;285:1574• Yang, X-M et al. JACC 2004;44:1103

Vinten-Johansen J, Zhao ZQ, Zatta AJ, Kin H, Halkos ME, Kerendi F. Postconditioning--A new link in nature's armor against myocardial ischemia-reperfusion injury. Basic Res Cardiol. 2005 Jul;100(4):295-310.

Vinten-Johansen J, Zhao ZQ, Zatta AJ, Kin H, Halkos ME, Kerendi F.Postconditioning--A new link in nature's armor against myocardialischemia-reperfusion injury. Basic Res Cardiol. 2005 Jul;100(4):295-310.

Kloner RA, Dow J, Bhandari A. Postconditioning markedly attenuates ventricular arrhythmias after ischemia-reperfusion. J Cardiovasc Pharmacol Ther. 2006 Mar;11(1):55-63.

Kloner RA, Dow J, Bhandari A. Postconditioning markedly attenuates ventricular arrhythmias after ischemia-reperfusion. J Cardiovasc Pharmacol Ther. 2006 Mar;11(1):55-63.

Kloner RA, Dow J, Bhandari A. Postconditioning markedly attenuates ventricular arrhythmias after ischemia-reperfusion. J Cardiovasc Pharmacol Ther. 2006 Mar;11(1):55-63.

Ventricular Arrhythmiaswith and without postconditioning

Kloner RA, Dow J, Bhandari A. Postconditioning markedly attenuates ventricular arrhythmias after ischemia-reperfusion. J Cardiovasc Pharmacol Ther. 2006 Mar;11(1):55-63.

Experimental protocol

Staat P, Rioufol G, Piot C, Cottin Y, Cung TT, L'Huillier I, Aupetit JF, Bonnefoy E, Finet G, André-Fouët X, Ovize M. Postconditioning the human heart. Circulation. 2005 Oct 4;112(14):2143-8.

Staat P, Rioufol G, Piot C, Cottin Y, Cung TT, L'Huillier I, Aupetit JF, Bonnefoy E, Finet G, André-Fouët X, Ovize M. Postconditioning the human heart. Circulation. 2005 Oct 4;112(14):2143-8.

Serum CK release over the first 72 hours of reperfusion

Copyright ©2005 American Heart Association

Blush grade and ST-segment shift during reperfusion

Staat P, Rioufol G, Piot C, Cottin Y, Cung TT, L'Huillier I, Aupetit JF, Bonnefoy E, Finet G, André-Fouët X, Ovize M. Postconditioning the human heart. Circulation. 2005 Oct 4;112(14):2143-8.

Potential Mechanisms of Postconditioning

A. Triggers including:1. Adenosine2. Opioids3. Erythropoietin4. Endogenous nitric oxide5. Reactive oxygen species6. Acetylcholine7. Tissue factors8. Pro-inflammatory cytokines and bradykinin9. Hydrogen sulfide

B. Mediators –Reperfusion injury salvage kinase pathways including:1. Phosphoinositide-3-kinase2. Extra-cellular signal regulated kinase (1/2) pathways3. Protein kinases G and C

C. End-effectors such as:1. Mitochondrial permeability transition pore2. Mitochondrial potassium ATP channel

Kaur S, Singh N. Molecular aspects of ischaemic postconditioning. Fundamental & Clinical Pharmacology 2009;23:521-536.

Piot C, Croisille P, Staat P, Thibault H, Rioufol G, Mewton N, Elbelghiti R, Cung TT, Bonnefoy E, Angoulvant D, Macia C, Raczka F, Sportouch C, Gahide G, Finet G, André-Fouët X, Revel D, Kirkorian G, Monassier JP, Derumeaux G, Ovize M. Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N Engl J Med. 2008 Jul 31;359(5):473-81.

Concordant improvements in coronary flow reserve and ST-segment resolution during percutaneous coronary intervention for acute myocardial infarction:

a benefit of postconditioning

• 24 patients with evolving anterior STEMI were randomized to ischemic postconditioning or usual care during PCI

• Postconditioned pts had a greater and more rapid resolution of ST segment elevation (70% vs. 48%, p = 0.0002) by the end of the procedure

• Postconditioned pts had greater hyperemic coronary vasodilator reserve (2.2 vs. 1.5, p< 0.001)

• Peak serum creatine kinase was lower in postconditioned pts (1,524 vs. 1,862 IU/L in controls, p = 0.03)

• Conclusion: Postconditioning performed during PCI for STEMI improved ST-segment resolution and coronary flow reserve, measures of microcirculatory function, as well as reducing tissue necrosis.

Laskey WK, Yoon S, Calzada N, Ricciardi MJ. Concordant improvements in coronary flow reserve and ST-segment resolution during percutaneous coronary intervention for acute myocardial infarction: a benefit of postconditioning. Catheter Cardiovasc Interv. 2008 Aug 1;72(2):212-20

Remote Ischemic Preconditioning or Ischemic Conditioning at a Distance

Ischemic conditioning of one vascular bed may protect a remote vascular bed. This could occur within the same organ or between different organs.

Regional ischemic preconditioning protects remote virgin myocardium from subsequent sustained coronary occlusion

• Przyklenk K, Bauer B, Ovize M, Kloner RA, Whittaker P. Regional ischemic 'preconditioning' protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation. 1993 Mar;87(3):893-9

Showed that “Brief episodes of ischemia in one vascular bed protect remote, virgin myocardium from subsequent sustained coronary artery occlusion in canine model.”

Regional ischemic preconditioning protects remote virgin myocardium

Przyklenk K. et al. Circulation 1993;87:893

Ischemic preconditioning at a distance. Reduction of myocardial infarct size by partial reduction of blood supply combined with rapid stimulation of the gastrocnemius muscle in rabbit.

• Birnbaum Y, Hale SL, Kloner RA. Ischemic preconditioning at a distance: reduction of myocardial infarct size by partial reduction of blood supply combined with rapid stimulation of the gastrocnemius muscle in the rabbit. Circulation. 1997 Sep 2;96(5):1641-6.

Showed that remote ischemia of a skeletal muscle could precondition the myocardium.

Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in

patients with acute myocardial infarction: a randomised trial

• 333 patients with first AMI randomized to primary PCI with or without remote conditioning (4 cycles of 5-minute brachial artery cuff inflation & 5 minutes deflation)

• Median salvage index by myocardial perfusion imaging 0.75 in remote conditioning group versus 0.55 in control group, p = 0.03

• Conclusion: Remote ischemic conditioning before hospital admission increases myocardial salvage and is safe.

Bøtker HE, Kharbanda R, Schmidt MR, Bøttcher M, Kaltoft AK, Terkelsen CJ, Munk K, Andersen NH, Hansen TM, Trautner S, Lassen JF, Christiansen EH, Krusell LR, Kristensen SD, Thuesen L, Nielsen SS, Rehling M, Sørensen HT, Redington AN, Nielsen TT. Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial. Lancet. 2010 Feb 27;375(9716):727.

Bøtker HE, Kharbanda R, Schmidt MR, Bøttcher M, Kaltoft AK, Terkelsen CJ, Munk K, Andersen NH, Hansen TM, Trautner S, Lassen JF, Christiansen EH, Krusell LR, Kristensen SD, Thuesen L, Nielsen SS, Rehling M, Sørensen HT, Redington AN, Nielsen TT. Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial. Lancet. 2010 Feb 27;375(9716):727.

Ischemic Conditioning

• Reducing myocardial infarct size• Reducing cardiac damage during percutaneous coronary

intervention• Protecting the myocardium during coronary artery bypass

grafting and other procedures requiring cardiopulmonary bypass

• Protecting the vasculature during vascular surgery procedures

• Unstable angina• Before activities that reproducibly cause angina in patients

with stable angina• Protecting donor hearts before excision and transport• Protecting other organs (brain, kidney) during episodes of

ischemia